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Screening creates drug customers. Keep this little-known consumer beware maxim in mind when you read the new finding about bone density retesting. Frequent screening bone scans, starting in early middle-age, have been the norm ever since osteoporosis was discovered in the 1980s. (Believe me, no one ever heard of osteoporosis before then, other than the few health professionals who cared for people of advanced old age.) The new study shows that women whose first test at age 67 indicates normal bone density can safely delay having a second test for as long as 15 years. There was a time, not so long ago, when women were advised to start bone density testing right after menopause. But then again, there was also a time when the diagnosis of osteoporosis was not made until a person suffered a fragility fracture.

Before I describe the new study, an historical context is in order. Merck, maker of the first osteoporosis drug, may also have been the first company to establish a winning “formula” for blockbuster drugs: 1) lower the cutoff point for the diagnosis of osteoporosis, better yet, fund a meeting in a beautiful place (like Italy) of high-profile osteoporosis researchers (aka, hired “consultants”) who will do it for you; 2) mount an “osteoporosis awareness” campaign to scare women into thinking the risk of hip fracture starts soon after menopause; 3) expand your market share with frequent mention of a new “disease” called osteopenia, a diagnosis that can be given to anyone who almost has osteoporosis; 4) encourage use of a new screening technology for identifying “at risk” women, and do it with an ad campaign that doesn’t mention your drug so it looks educational; 5) provide financial incentives to doctors who want to purchase screening equipment for their offices; 6) introduce your new drug Fosamax, which received FDA approval in 1995 and soon became a top-selling drug worldwide, despite its minimal effectiveness in reducing the chance of having a hip fracture (1%). For more, read “The Marketing of Osteoporosis.”

Now for the study that appeared today in The New England Journal of Medicine. It followed nearly 5,000 women, 67 or older, with normal bone density at the hip and no history of hip or spinal fractures, or osteoporosis treatment. The research team led by Margaret L. Gourlay, MD, University of North Carolina, took off from the current advice that women should start having bone-density tests at age 65. This study was designed to determine how long it took for osteoporosis (defined as bone mineral density T score, −2.50 or lower) to develop in women with normal bone density or osteopenia.

The women were followed for 10 to 15 years. The findings were unexpected, according to Dr. Gourlay, who told the New York Times that she and her colleagues were surprised by how slowly osteoporosis progressed. Osteoporosis developed in fewer than 10% of the women who started the study with normal bone density and in fewer than 10% who had either “mild or moderate osteopenia.” (And I was surprised that the New England Journal of Medicine would allow researchers to use the industry-created term osteopenia.) In summary, women with normal bone density or “mild osteopenia” at age 67 can safely delay having a second bone density test for 15 years.

I hope that word gets out to women about this study because it should cut back on the overuse of bone-density tests, as well as the overuse of Fosamax and other drugs in the same class called bisphosphonates (e.g., Boniva, Actonel, etc.). The test was initially portrayed to women and doctors as predictive of who is likely to suffer a hip fracture. But Canadian consumer advocate Barbara Mintzes, University of British Columbia, had a more realistic take on this claim over ten years ago: “Bone mineral density testing is a poor predictor of future fractures, but an excellent predictor of start of drug use.” The overwhelming majority of hip fractures, by the way, occur after the age of 70.

Something to think about: Most medical research is now funded by industry, particularly the companies that make drugs, devices, and testing equipment. This study was funded by the U. S. National Institutes of Health.

For information about these serious adverse events associated with these drugs, read “Drugs for bone loss.” And read this to learn why women should stop taking them after five years. And here is Dr. Susan Love’s description of how bisphosphonate drugs work and why no one should be surprised that they are causing problems.

This post has been revised to reflect the following correction, added January 21, 2012.

The first version of this article, posted January 19, misstated the conclusion of this study. The authors did not specify when women should be retested. The original title of this post and the post itself have been changed accordingly.

First, a trip down memory lane on the use of bone drugs for the prevention of hip fractures. It is now 16 years since Merck’s widely prescribed Fosamax went on the market. In time, it was prescribed inappropriately to women with so-called “pre-osteoporosis” or osteopenia (yet-another drug maker invented “disease”). It was also prescribed inappropriately to women in their early 50s, thanks to Merck’s marketing strategies that made us think we would start crumbling inside right after menopause. Then came the reports of osteonecrosis of the jaw and spontaneous thighbone fractures in some women on Fosamax. And now, the latest bulletin on Fosamax and its knock-offs like Actonel, Reclast, and Boniva: If you have been on one of these drugs for five years, stop taking it.

What has happened to send out word that five years is enough and longer would be too risky? Two things: a paper by bone physiologist Susan Ott, MD, in the Cleveland Clinic Medical Journal published this month and the recent announcement that two FDA advisory panels will conduct a comprehensive safety review of the research supporting the use of these drugs called bisphosphonates. As noted often on this website: drug makers conduct the FDA-required studies of their own products; a new drug’s effectiveness is carefully studied to determine whether it is better than nothing, i.e., a placebo; and the full story on a new drug’s adverse reactions comes many years later, if at all.

Members of the FDA advisory committee that met early this month agreed that a time limit should be put on the duration of bisphosphonate therapy, but they could not agree on what that time limit should be. Anyone currently on a bisphosphonate drug should not wait for the FDA; and instead, go with Dr. Ott’s advice to stop taking the drug after five years. Her newly published paper entitled, “What is the optimal duration of bisphosphonate therapy?” is an in-depth assessment of all studies in which one of these bone drugs was compared with a placebo, as well as observational studies. Here is her conclusion:

Almost all the data about the safety and efficacy of bisphosphonate drugs for treating osteoporosis are from patients who took them for less than 5 years. Reports of adverse effects with prolonged use have caused concern about the long-term safety of this class of drugs. This is particularly important because these drugs are retained in the skeleton longer than 10 years, because there are physiologic reasons why excessive bisphosphonate-induced inhibition of bone turnover could be damaging, and because many healthy postmenopausal women have been prescribed bisphosphonates in the hope of preventing fractures that are not expected to occur for 20 to 30 years.

As someone who regularly visits Dr. Ott’s website (see below), I know that she has long been a supporter of appropriate use of bisphosphonates. The reason was given in her newly published paper: These drugs “reduce the incidence of devastating hip fractures”

I’ll stop quoting Dr. Ott right here to explain the operative words in her statement: reduce the incidence. This careful choice of words that is unlikely to be explained by many prescribing doctors. Consequently, many women go on bisphosphonate therapy mistakenly thinking they will not a have hip fracture. In truth and at best, only a small percentage of women who go on three to five years of bisphosphonate therapy will avoid a fracture.

One of the first important clinical trials to compare Fosamax with a placebo is the FLEX trial. After four years the FLEX trial found that 1.1% of the women in the placebo group had a hip fracture and 0.9% of the women taking Fosamax. Yes, that tiny fraction of a difference between taking Fosamax and going without treatment is what osteoporosis researchers get excited about. (If this described a woman’s chance of developing a serious drug side effect, it would be characterized as “rare.”)

The drugs always look better in osteoporosis studies when the authors throw all types of fracture (hip, forearm, spine, etc.) together. Again, using data from the FLEX trial: 21.3% of women on placebo had any type of fracture, compared with 19.9% of the women on Fosamax.

You might ask: Why haven’t I heard this before? Why do researchers report such findings as “significant”? Answers: Many prescribing doctors themselves don’t understand biostatistics; the word significant—to researchers—means “not due to chance,” the statistics can be trusted. Also, researchers tend to look at things in public health terms: a fraction of a 1% benefit means a lot when an estimated four million women in the U.S. are taking a bisphosphonate.

Back to Dr. Ott, who acknowledges “some emerging evidence of harm after 5 years of bisphosphonate treatment; to date the incidence of serious side effects is less than 1 in 1,000, but the risks beyond 10 years are unknown.” The serious side effects include spontaneous thighbone (femur) fracture, osteonecrosis of the jawbone.

The most obvious candidates for bisphosphonate therapy, according to Dr. Ott, are women whose risk of hip fracture is higher than 3% in the next decade and elderly women who already had compression fractures of the spine or a hip fracture. As for the risks the latter group might suffer, “women with a vertebral fracture have a one-in-five chance of fracturing another vertebra, which is a far higher risk than any of the known [emphasis mine] long-term side effects from bisphosphonate.

She is against prescribing bisphosphonates to women with osteopenia who have not had a fragility fracture, saying this common use is “based on hope, not evidence.”

It’s never fails to amaze me how long a drug can be in use before its benefits and harms are fully understood. This is particularly troubling where it concerns drugs given to healthy people to prevent something that might happen to them sometime in the future. On my mind right now is the bone drug Fosamax prescribed since the mid-1990s to symptomless women with bone loss usually detected on a bone density measurement test.

Concern over the lack of good information about this widely prescribed drug and it multiple knockoffs (Actonel, Boniva, Didronel, Reclast, Aredia) has galvanized several research teams around the world. The impetus is the unusual thigh bone fractures initially reported over six years ago in women taking Fosamax click here. The international researchers analyzed all relevant studies to determine whether these bone drugs “prevent or cause bone fractures”. Their unenthusiastic conclusion: The drugs have “some effectiveness” in preventing vertebral fractures in the short-term (one to three years). Brace yourself for this clarification: Effectiveness is limited to “vertebral fractures demonstrated by x-ray” (translation: tiny symptomless spinal fractures that the women themselves are unaware of). The researchers go on to point out, “The efficacy with regard to preventing hip fractures is uncertain.”

Wait a minute…wasn’t hip fracture prevention the big selling point of Fosamax and its knockoffs? Remember those scary statistics indicating how many of us would die within the year of a hip fracture.

The harms of these bone drugs are usually determined to be rare, for example, the rotting jawbones (osteonecrosis of the jaw) of women given oral surgery while on Fosamax click here. So are the esophageal ulcers and those spontaneous thigh bone fractures we’ve been hearing about for at least five years. Has anyone tallied up all these “rare” harms so they can be weighed against the small, uncertain benefits of bone drugs? The researchers addressed this question, but said, in effect, “Hold off, we still don’t have a good count yet”. In other words, people on one of these bone drugs are participating in one long, ongoing experiment.

Most of the studies, by the way, were done on Fosamax because it has the longest track record. There is no evidence that the other drugs in this class known as bisphosphonates are any safer or more effective because no head-to-head comparison has been done.

In case you’re wondering how these drugs got FDA approval in the first place, the new analysis gives a brief history. Merck, maker of Fosamax, had only to prove its drug increased bone density… on the shaky assumption that this would translate to fracture prevention. (To gain FDA approval, drug makers test their products against a placebo which means they need only to prove their drug is better than nothing.) In time, the aforementioned x-ray evidence of fracture reduction became acceptable proof of a bone drug’s effectiveness. Only a third of the people with vertebral fractures that show up on x-ray have symptoms.

By 2006 long-term data came from a trial, known by its acronym FLEX, that followed women taking Fosamax for three to ten years. The aim of this trial was to determine whether Fosamax can achieve what matters most to women taking this drug: Does it reduce hip fractures? It found no significant difference between Fosamax and placebo in terms of preventing any type of fracture.

And so it goes. This new analysis is available online at Therapeutics Initiative, published by the University of British Columbia (UBC), Vancouver, click here. It is based on the combined findings of the Cochrane Collaboration and other independent groups in France and Spain. The conclusion: “Given that bisphosphonates can cause severe adverse effects including fractures, which they are meant to prevent, it is urgent that the overall benefits and harms of long-term treatment be clarified. The available evidence suggests that the benefit-harm balance may be unfavorable for their use in osteoporosis.”

The UBC research team plans to take it from there and conduct “a full systematic review and critical appraisal of this widely prescribed class of drugs.”

More to consider about these drugs
-If you have no bone symptoms and have decided that you’ll never take one of these drugs, think twice about having your bone density measured. This screening test is all about unproven predictions of who will suffer a fracture after age 70 and directing them to long-term drug therapy.

-If you think you’ve been injured by a bisphosphonate drug, contact the FDA’s Medwatch Program click here.

Remember those scary reports of spontaneous thighbone fractures that occurred in some women who were taking fracture-prevention drugs like Fosamax? The bone breaks for no apparent reason. (In one memorable case, a woman said her thighbone broke while standing in a stalled subway train that lurched suddenly.) Such fractures are described as very rare (0.03%), according to a new analysis of the data generated by three large trials. These are the same clinical trials that proved bone drugs like Fosamax and Zometa are more effective than no treatment (placebo) in reducing hip fracture—the most serious complication of osteoporosis. Now the results of these trials were searched solely for the rate of spontaneous thighbone fracture.

It’s a relief to know that this is “a very rare” side effect of osteoporosis drugs. But looking at these trial results again reminds me that their hip fracture prevention benefit is also pretty rare. The first to win FDA approval was Fosamax (generic name: alendronate), produced by Merck. After three years, only 1% fewer drug-treated women suffered a hip fracture, compared to untreated women. The drugs’ effectiveness looks much better when the company-sponsored researchers throw in fractures in other sites—spine, wrist, and forearm. In one osteoporosis research sleight of hand that’s always bothered me, it is common to count a reduction in spinal fractures that are symptomless and can be seen only on X-ray.

But I digress. Back to the spontaneous thighbone fractures and how we now know they are very rare. The three major trials that provided the data for this conclusion had a combined total of 14,195 women randomly assigned to take either a placebo or a bone drug (Fosamax in two trials, Zometa in one). Keep in mind that most of what are called hip fractures are actually breaks in the “neck” of the femur, or thighbone, where it meets the pelvis in the ball and socket joint.

So here’s final count: Of the 284 women who had hip or femur fractures, only 10 had what’s called atypical thighbone fractures. It’s interesting to note how few hip or femur fractures—atypical or not—occurred, considering that the 14,195 study participants were considered to be at high risk for fracture and between the ages of 65 and 80 years when they entered the study. Could it be that this isn’t the biggest health threat we face in old age? Or could it be that the study participants weren’t followed long enough?

This analysis appeared in The New England Journal of Medicine and was funded by Merk and Novartis (maker of Zometa). How long can people safely take this drug is not answered by this analysis. It’s a question that lingers over all bone drugs called bisphosphonates (other brand names: Boniva, Actonel, Reclast). The authors of this analysis conclude that the risk of spontanous thighbone fracture remains rare “even among women treated with bisphosphonates for as long as ten years.” Buried deep in this paper, however, is the fact that few women were followed this long. The majority were followed only three to four years. Women on long-term bisphosphonate therapy are advised to report thighbone pain immediately to their doctors as this was the telling symptom that preceded a spontaneous fracture.
For more information
To determine whether you can benefit from Fosamax or any other bisphophonate drug, see this chart from the Cochrane Collaboration, which is based on the results of the above-mentioned three clinical trials. You will see that women who have been diagnosed with low bone density or who have broken bones in their spines are more likely to benefit than those whose bone density is near normal (osteopenia) or who do not have spinal fractures. click here

Back pain and the herniated disc:
An interview with Richard Deyo, back-pain researcher and primary care physician

By Maryann Napoli

Low back pain has generated thousands of published studies, so it was surprising to read that so little has been proven about the best way to diagnose something as common as a herniated disc. That was my first thought when I saw the new Cochrane review of all studies that had assessed the diagnostic accuracy of the various components of the physical exam. Sixteen studies in all, most of them old and only one conducted in primary care practice where most people start looking for help. The combined total of 2,504 study participants had back pain with leg pain, aka sciatica. The conclusion: no single test can accurately diagnose a herniated disc, so doctors should use all of them to do the initial physical exam.

To clarify a few things, I turned to one of the co-authors of the new Cochrane review, Richard A. Deyo MD, MPH, Kaiser Permanente Professor of Evidence-Based Family Medicine, Oregon Health and Science University, Portland. Dr. Deyo, arguably the country’s leading back pain expert who has co-authored over a 100 published studies about the treatment of back pain.

MN: You didn’t have much to work with in this Cochrane review. All but one of the studies weren’t that great, but it gave me an excuse to call you so I can interview you again (click here for 2007 interview with Dr. Deyo).

RD: Yes, like most Cochrane reviews about diagnostic tests, it focuses one-by-one on physical examination signs and of course, doctors never do just one physical exam test. We do several tests and combine it with a history and it all forms a picture that is more reliable than just one test. For back problems, this might include tests of strength in the lower extremities (such as flexing the foot up or down), Achilles reflexes, the straight-leg raising test, and sensory testing (touch).
MN: How important is it to determine whether a herniated disc is the source of back pain, especially now that we know, in most cases, it will go away in time? Two landmark randomized clinical trials showed that 75% of people with the severe back and leg pain of a herniated disk got better without surgery by three months.

RD: That’s a fair question, and it is fair to say that there is usually no urgency in finding out whether the disc is the problem. But it is helpful in giving the patient a prognosis. If it’s a herniated disc we know what to expect with and without surgery.

MN: You’re referring to the two landmark studies.

RD: Yes, if the patient appears to have a herniated disc I would follow the patient a little more closely than I would the person with run-of-the mill back pain. Beyond that, if it looks like the person isn’t getting better, he or she might consider surgery. Then, using data from the studies you just cited, [I would let] the patient know that the surgery might speed up recovery but after a year or two, [he or she will] probably be in the same place with or without surgery. [And the patient] would then have to consider: how do I feel about the risks of the surgery and the urgency of resolving my symptoms?

MN: Back pain is an area rife with overtreatment. To protect yourself from overtreatment, what kind of a physician should you see first?

RD: I’m biased because I’m a primary care physician. I think the first stop should be the primary care physician, as opposed to referring yourself right off the bat to an orthopedic surgeon.

MN: Why?

RD: The primary care physician should be able to do good examination to be sure you don’t have a serious underlying problem like cancer or an infection and be able to explain a range of options without having any vested interest in any particular approach. I make a distinction between back pain alone and back pain with leg pain. If the patient has back pain alone, that suggests surgery isn’t going to help much and [steroid] injections aren’t going to help much. In most cases, the best approach is self-care and exercise after acute pain subsides and it’s probably unwise to think about the more invasive treatment. People with back and leg pain are also likely to get better without any invasive treatment, and if they don’t, they should understand what the options are.

MN: There’s a lot of evidence that MRIs and CT scans are overused and concern about the high-dose radiation exposure from CT scans. (Click here for information about radiation exposure from CT scans.)

RD: Yes, part of the problem is patients often want these tests. They say, “I want to know what’s wrong.” And the fallacy is these tests so often show abnormalities that have nothing to do with the back pain. And they might lead you down a garden path to treatments that may not help. Most people don’t realize that about a quarter of us under the age of 60 have a herniated disc, but no back pain, no leg pain, no nothing. So when a doctor sees that on a CT scan by itself, it may not mean much unless it matches up with leg pain down the same side as the disc and in the same level as the disc, etc. The history and the physical exam have to match up with findings on the scan for it to mean anything. Another thing people don’t realize is that bulging discs are normal. Bulging discs and degenerated discs are in just about everyone over the age of 60 and in people under 60, probably half of them.

MN: What are the latest fads in the overtreatment that you may want to warn us about?

RD: It seems like there’s a new one every day. Are you familiar with vertebroplasty?

MN: Yes, the injection of a cement-like substance into spinal fractures due to osteoporosis.

RD: Two studies, published in the same issue of the New England Journal of Medicine, indicate that this treatment is no more effective than a local anesthetic injection, yet it had become very popular. This is just one example of something that often happens—new technologies that are introduced and become widespread before they are carefully evaluated.

MN: What else gets your hackles up?

RD: Latest thing is artificial discs, which are now touted for patients with degenerative disc disease. It’s like a sandwich with metallic plates—it’s a sandwich with polyethyene plastic material in between to form sort of a cushion. It is inserted between the vertebrae after [the surgeons] shell out the natural material. It’s being touted for people who just have degenerated, or worn-out, discs and back pain—not necessarily a herniated disc. It’s touted for anyone with back pain and a degenerated disc, which describes just about everyone over the age of 50.

MN: And I assume this, too, has not been evaluated.

RD: In my view, it is not adequately studied. The FDA approval was based on the finding that artificial discs are “not inferior” to spinal fusion surgery. The companies did two randomized trials comparing artificial discs with spinal fusion. The problem is we don’t know how long these artificial discs last or what the long-term complications may be. And even more fundamentally, they were compared with spinal fusion, but it’s not clear that fusion is effective.

MN: What about epidural steroid injections?
RD: There’s been an explosion in their use over the last decade. But when you look at the randomized controlled trials that compared epidural steroid injections with placebo injections [just saline], here’s what the research shows: half the trials show no difference, and half the trials show a small advantage for the steroid injections. None of these trials show that these injections help people avoid surgery. A fair conclusion is they offer some people with sciatica temporary relief, but they have no role in the treatment of back pain alone, that is without leg pain, although they are commonly used in that situation.
MN: What have you published recently?

RD: I co-authored an acupuncture and back pain study that was published last year in Archives of Internal Medicine. All the patients were “blinded,” so they couldn’t see which of three treatments they were receiving for back pain. One group got real acupuncture; another group was poked with a toothpick [sham acupuncture]; and another group received usual care from their primary care physicians. The real acupuncture and the sham acupuncture were identical in terms of results. Both groups did better than the group that got usual care from their usual primary care physicians. One interpretation of our results could be: it’s all placebo effect. Another interpretation could be that stimulating acupuncture points stimulates some physiological response whether the skin is penetrated or not. Our results are similar to that of several German studies that also showed sham and real acupuncture are better than the usual care.

For decades, osteoporosis prevention meant drugs, estrogen, and calcium supplements—all of which we now know are better at increasing bone density than actually reducing hip fractures. Some osteoporosis researchers have taken a different approach: concentrate on ways to prevent elderly people from falling which can, in turn, prevent other injuries as well as hip fractures. This school of thought just got a major boost from the pooled results of eight clinical trials that found high doses of vitamin D3 supplements can cut the chances of falling by up to 26%. Unexpectedly, calcium supplements did not seem to be important to this benefit. Most impressive, the analysis indicates that muscle weakness is reversible in elderly people.

Muscle weakness has long been known to be a key risk factor for falls, and vitamin D is known to improve muscle strength. But there were lingering questions regarding the best type of vitamin D and the appropriate dose for the prevention of falls. They are answered by a new meta-analysis of eight trials, published early this month in the online version of the British Medical Journal. An international team headed by H.A. Bischoff-Ferrari, University of Zurich, Switzerland, identified eight trials in which women and men, age 65 years and older, had been randomly assigned to take either a placebo or some form of vitamin D in doses ranging from 200 to 1,000 International Units (IU) a day, with or without calcium. Trials lasted from 9 to 36 months.

No fall reduction benefit was found in the people who had been taking vitamin D in doses less than 700 IU daily. When the researchers singled out the trials with the highest quality for fall assessment (i.e., five of the eight trials), the best results were shown in the trials that involved high doses of vitamin D3 (cholecalciferol). “38% of individuals treated with 700-1000 IU vitamin D3 had at least one fall versus 50% of individuals in the control group taking calcium or placebo,” explained Dr. Bischoff-Ferrari in an e-mail. This benefit showed up within two to five months of the initiation of treatment.

Dr. Bischoff-Ferrari and colleagues did not rule out the possibility that vitamin D doses higher than 1,000 IU daily could be even more effective. No high-quality randomized trials have explored this possibility. The new findings support the vitamin researchers in the U.S. who, for years, have been calling for an increase in the recommended daily allowance, which is 200 to 600 IU.

And what about that no-effect finding for calcium? This will come as a surprise to older women who have long been told to take at least 1200 mg calcium daily to avoid osteoporosis. Dr. Bischoff explained, “Vitamin D increases the uptake of calcium. If one has more vitamin D, [the] calcium uptake is more efficient and less calcium may be sufficient. That does not mean that we do not need calcium — calcium is important for bone — but it means that when we get sufficient vitamin D, we may lower the recommendations for calcium intake. In clinical practice this may offer the opportunity to recommend vitamin D supplementation in combination with a ‘bone healthy diet’ covering calcium needs by milk products and vegetables rich in calcium. This is possible if the target intake of calcium is 700 mg of calcium per day rather than [current recommendation of] 1000 to 1500 mg per day.” Dr. Bischoff-Ferrari backed up these assertions with two recently published research papers that came with her e-mailed responses.
More information:
People fall for a variety of reasons, including over-sedation with prescription drugs. For more about this and the minimal efficacy of Fosamax and other bone drugs, see our 2008 article entitled, “Osteoporosis: many drugs prescribed, not so many hip fractures avoided.” and our 2005 article entitled,”Vitamin D defiency—cause of many ailments.”

How a risk factor (bone loss) became a disease (osteoporosis) by Maryann Napoli. Originally published in American Journal of Nursing, May 2009

Nurses probably get the same question I often get as a consumer advocate. Should I be on this drug? You’re asked because you’re seen as the expert or simply a knowledgeable friend. In fact, it’s a valid question not only to ask but also to look beyond the prescribing health care provider for answers.

In the name of prevention, millions of Americans have accepted the idea that it is reasonable to treat a risk factor (e.g., high cholesterol, bone loss) as if it were a disease. Think back to the 1990s when virtually all menopausal women were advised—pressured, according to accounts that came my way—by their gynecologists to go on hormone therapy to prevent heart disease and hip fractures.

More people should question the wisdom of going on long-term drug therapy. Often the magnitude of the risk factor has been overestimated; or the danger of the disease itself may be exaggerated by people trying to sell us something—like a drug you must take for the rest of your life.

Osteoporosis provides an excellent example of how the pharmaceutical industry begins creating a market for a new prevention drug years before it is approved. The disease has become a major health concern for older women, though it was unknown to the general public until the early 1980s when the drug industry-led awareness campaign began. It used to be that osteoporosis was not diagnosed until a fragility fracture had occurred.[1]

But a new definition, one based on bone mineral density, was established in 1993 at a World Health Organization meeting of osteoporosis researchers. Its ostensible purpose was to determine the global prevalence of osteoporosis, but this meeting is where the definition of osteoporosis was radically changed. What had been simply a risk factor (bone loss) became a disease (osteoporosis), complete with an arbitrary cutoff (bone density more than 2.5 standard deviations below the normal bone mass in young women).[2]

Overnight, the market for bone drugs had been expanded. Years after that WHO meeting, I would learn that it was sponsored by several pharmaceutical companies.2 Hormone drugs were the standard preventive treatment at the time of the meeting, but three years later the first non-hormonal drug for bone loss—alendronate (Fosamax)—was launched.

Getting symptom-free women to accept drug therapy requires scarey statistics that imply the danger period starts right after menopause, leaving the impression that hip fractures, the most disabling consequence of osteoporosis, often occur soon after the hot flashes are over. Here’s one stat you would see often: 24% women, aged 50 and over, die within a year of a hip fracture.[3] And here’s one you don’t see often: over 90% of the hip fractures occur in people over 70 and the average age is 80.[4] Elderly men have hip fractures, too, but the early marketing of alendronate was all about the ladies.

How Predictive are Bone Scans?

In the initial phase of the industry-funded osteoporosis awareness campaign, the scan known by the acronym DEXA was advised for women at the time of menopause. Scanning caught on in a big way, especially after Merck, the maker of alendronate, began financing the installation of DEXA machines in doctors’ offices.[5] Nothing creates drug customers faster than getting people to be routinely scanned.

Unfortunately, scanning is not good at predicting which women in their early 50s will have a hip fracture at age 80. This was known in 1997 thanks to a report from the British Columbia Office for Health Technology Assessment, which—to my knowledge—is the first to reveal industry sponsorship of that 1993 WHO meeting where osteoporosis was redefined.[6]

Unfortunately, the report had no effect on U.S.testing guidelines, but consumer advocate Barbara Mintzes, Universityof British Columbia, summed up the situation nicely, “Bone mineral density testing is a poor predictor of future fractures, but an excellent predictor of start of drug use.”[7] Merck’s ads aimed at women did not even mention alendronate, they simply said, “Ask your doctor whether a bone density test is right for you.” Sure, low calcium/vitamin D intake, scatter rugs, poor muscle strength, certain medications, impaired vision were given lip service as contributing factors to osteoporotic fractures, but loss of bone density always seemed front and center.

How Good is the Drug?

In the initial phase of DEXA promotion, many women in early middle-age, with low bone density but no history of fracture, were put on alendronate, despite the fact that the drug was tested only in elderly women with vertebral fractures. The results, even for this supposedly high-risk elderly group, were not impressive. In the Merck-sponsored three-year trial that received Food and Drug Administration approval, hip fractures occurred in 1% of those on alendronate, compared with 2% of those on a placebo. [8] (A “50% reduction in hip fracture” is the accurate, though misleading, way these results were often portrayed.)

Here is where the nurse/advocate can serve as a sounding board for patients deciding whether to go on drug therapy, helping them consider questions like: Are you similar in age and fracture history to the women in this trial? What does that 1% fewer hip fractures mean to you? Let’s compare that 1% benefit with the 1.5% risk for a alendronate-induced esophageal ulcer found in this trial? Consider what happened to the study participants who did not take alendronate (98% of the untreated women—i.e., the placebo group—did not have a hip fracture). The “script” for this discussion is the drug’s official FDA-approved label and the Physicians’ Desk Reference where the trials that won FDA approval are described.

When alendronate was put to the test for elderly women with bone loss but no vertebral fractures, the four-year trial showed that the hip fracture rate was no different for the drug-treated participants than it was for the women taking a placebo.In short, the drug is good at improving bone density but not so good at reducing hip fractures. This did not stop other drug companies from introducing their own alendronate knockoffs—risedronate, ibandronate, pamidronate, etidronate and zoledronic acid. All are in the same drug class called bisphosphonates. In an example of how long a drug has to be on the market before the full picture of harm is known, the FDA reported early this year that all bisphosphonates carry the risk of severe and sometimes incapacitating musculoskeletal pain.[9]

Drug Ad Campaign Misled Doctors

Why younger rather than elderly women became the likely recipients of a bisphosphonate prescription is no mystery. Merck’s initial ads aimed at physicians encouraged it. A multi-page glossy ad campaign that ran frequently in Annals of Internal Medicine featured a thin fortysomething white woman with a crumbling ancient stone column in the background. “Don’t wait for a fracture… No matter what her degree of osteoporotic bone loss…” [10] I wrote to the editor-in-chief of Annals, pointing out that alendronate had no proven benefit for women in early middle age. Never got a reply, but Annals stopped running the ad about six months later. Still, the message had already gone out, there and elsewhere—early middle age is the appropriate time to start fracture prevention with alendronate. From the drug industry’s point of view, the younger customer is far more desirable than, say, the elderly nursing home resident with a limited remaining lifespan in which to take drugs.

Today, women in the osteoporosis drug ads are usually in their early sixties. The guidelines for bone density measurement currently recommend bone mineral testing not begin before age 65 (or 60 in some high-risk cases)[11], but now there’s a bigger problem. Researchers have known, at least since 2000, that bone strength or bone quality are better predictors of hip fracture than bone density. In 2001, the National Institutes of Health redefined osteoporosis as a combination of bone mineral density and bone quality. But there is no test for bone quality or bone strength. 1

It’s going to take time for the word to get out.

How relevant is this story to other drugs people take to treat a risk factor? In a word: very. Three-fourths of all Americans on cholesterol-lowering statins, the country’s top-selling drugs, do not have heart disease and are thus far less likely to benefit than people who do. [12] (Statins are terrific at lowering cholesterol, but much less impressive at reducing the risk for heart attack[13]—sound familiar?) The thresholds for high cholesterol[14] and high blood pressure were lowered several times over the years, each time making millions more people eligible for drug therapy. 5

Drug ads and industry-sponsored “education” programs are no longer the only major sources of biased information. Industry funding compromises the directives of non-profits like the American Heart Association and the American Cancer Society, as well as the experts who write treatment guidelines. [15] One example of the latter: eight of the nine doctors who served on the 2004 government committee that expanded the guidelines for cholesterol-lowering drug therapy had financial ties to statin companies.[16]

More than ever, nurses must be knowledgeable advocates for their patients. You may be the last of the independent health professionals.

“The increase in CT [scan] use and in the CT-derived radiation dose in the population is occurring just as our understanding of the carcinogenic potential of low doses of x-ray radiation has improved substantially, particularly for children.”

The low-dose in this quote is relative to the amount of radiation absorbed by atom-bomb survivors—long the only yardstick available to radiation-safety researchers. It appeared in a 2007 report in The New England Journal of Medicine which states that, contrary to conventional medical wisdom, the doses received by a CT scan carry a small but definitive risk of cancer. The lead author is David J. Brenner, PhD, Center for Radiological Research, Columbia University Medical Center, New York.

The radiation dose from a CT scan is far larger than that of a conventional x-ray because it typically involves 64 “slices” of radiation exposure, compared to one or two views of a standard x-ray. The American Heart Association, not known for warning the public about the negative aspects of medical care, acknowledged recently that the amount of radiation from a heart scan is equivalent to 600 chest x-rays.

Each scan creates an additional lifetime risk of cancer that is somewhere between 1 in 200 and 1 in 5,000, according to Dr. Brenner. Unfortunately, consumers who try to get information about radiation exposure from their doctors are unlikely to get an accurate answer. In a 2004 survey of radiologists and emergency room physicians, 75% of the entire group significantly underestimated the radiation dose from a CT scan. Worse, 53% of radiologists and 91% of the E.R. doctors did not believe that CT scans increased the lifetime risk of cancer.

Massive Increase in Scans
The large amount of radiation that concerns researchers like Dr. Brenner is due to the technology itself, as well as the alarming increase in usage. An estimated 62 million CT scans are now done annually in the U.S., up from 3 million in 1980. Lately, heart scans have become a source of alarm. The installation of cardiac scanning equipment has tripled in the U.S. in the past two years.

A recent international study in the Journal of the American Medical Association is the first to look at the radiation dose from a heart scan, aka cardiac CT angiography, as it is performed in the real world. The 50 study sites included in this research project were 21 university hospitals and 29 community hospitals. The research team led by Jorg Hausleiter, MD, found doses varied widely according to the equipment and the study site. Worst of all, the available strategies for reducing doses were not being used.

One of the obvious recommendations to emerge from this study is: “Low voltage scanning should be considered, especially for patients who are non-obese and at higher risk of radiation-associated cancer, such as children and young women.”

No one would deny that CT scans are an excellent diagnostic tool that may well have saved many lives. The problem is the complete lack of information. As often happens in the U.S., enthusiastic reception of a new technology—by doctors and consumers alike—precedes the science that would identify those people for whom the benefits outweighs the risks.

In many cases, the purportedly new, improved scan has never been proven in a large clinical trial to be better than the older, less expensive tests. Our profit-driven medical care “system” encourages the premature introduction and widespread acceptance of a new, costlier procedure. Add to the mix, entrepreneurial physicians who co-own the scanning equipment and have a financial incentive to overuse it.

Screening Uses Questioned
The first place to start questioning CT scans, according to Dr. Brenner, is their use for symptomless people. Healthy people are the ones most likely to harmed because they would incur the risks of a high radiation dose and overdiagnosis to receive an uncertain benefit. None of the following screening scans has been proven to be life-saving.

CT colonography, or “virtual colonoscopy,” is often regarded as a less-invasive alternative to the standard colonoscopy. It’s unlikely that many people who choose this method of colon cancer screening are informed of the high radiation dose or its penchant for finding abnormalities in nearby organs that lead to other investigations, some quite risky, that often prove to be benign (i.e., overdiagnosis).

CT lung screening for smokers and former smokers: This relatively new technology has become popular, despite the lung scan’s ability to find non-lethal cancers that are usually treated. A large ongoing government-sponsored clinical trial that has randomly assigned smokers and former smokers to a spiral CT lung scan or no scan will provide answers to two questions for this select group of individuals: Will regular scanning reduce their death rate? Will it cause more harm than good? Added 2011: Lung screeningscans for heavy smokers reduce lung cancer deaths.

CT whole-body screening: This is a truly awful idea promoted by Oprah Winfrey and advertised directly to the public on the radio, the Internet, and in newspapers. A whole-body scan will extend all the radiation and overdiagnosis problems cited above to the rest of the body.

Heart Scans may make sense for people with symptoms like shortness of breath and chest pain. They are not useful, however, for predicting a heart attack or stroke in people without symptoms. Constrictions in the coronary arteries that show up in the heart scans of symptom-free people are not where a future heart attack will occur (though interventional cardiologists have been opening these constrictions for years on the now-discredited belief that they are saving the patient’s life). A heart attack occurs when bits of plaque break away from the arterial wall and blocks the blood flow to the heart. Scans cannot identify which blockages will rupture.

Dentists have been in the forefront of identifying a severe complication of Fosamax, the osteoporosis drug widely prescribed to prevent fractures. The January issue of the Journal of the American Dental Association published a study describing a significant risk of osteonecrosis of the jaw from even oral use of Fosamax. Until this small study of 208 dental patients was published, jaw osteonecrosis was thought to be rare and limited to people with cancer who received large doses of Fosamax intravenously to treat bone metastases.

Dental School Patients Studied

In this study conducted at the University of Southern California School of Dentistry, 4% of the dental patients taking oral Fosamax had osteonecrosis of the jaw. All had suffered dental trauma—either a tooth extraction or ill-fitting dentures that resulted in jawbone exposure; all were women, average age 73 years, who had been taking the drug for 12 months or longer. Osteonecrosis is defined as “the presence of exposed bone in the mouth, which fails to heal after appropriate intervention over a period of six or eight weeks.”

Parish P. Sedghizadeh, DDS, and colleagues at the USC School of Dentistry found no cases of osteonecrosis of the jaw among their 4,384 dental patients not taking Fosamax who underwent tooth extraction. Fosamax was the first and most aggressively promoted of all drugs in a class called bisphosphonates, which also includes Actonel, Boniva, Aredia, Zometa, Reclast, and Bonefos. In 2011, the FDA issued a warning about serious adverse effects, stating that they apply to all bisphosphonates.

4% Risk is Not Rare

Sedghizadeh and colleagues say their findings contradict Merck’s claim that jaw osteonecrosis is a rare side effect of its drug. “We have been told that the risk with oral bisphosphates is negligible, but 4% is not negligible,” said Dr. Sedghizadeh. (The benefit of Fosamax could also be described as rare because the drug reduces the risk of hip fracture from 2% to 1%, as demonstrated in premarketing trials.) Prior to receiving FDA approval, Fosamax was tested in trials that lasted only three to five years. Ever since this drug first came on the market in 1996, the unanswered question has been: How long can people safely take Fosamax—or any one of other bisphosphonates, which are known to suppress bone turnover.

Drugs Have a Long Half-Life

This warning came from the USC Dental School research team: Bisphosphonates have half-lives of ten years or more, and people taking the drug orally may ultimately reach the same high dose level as that given intravenously to treat bone metastases in cancer patients. Sedghizadeh and colleagues also explained that because bisphosphonates stay in the bone for a long time, the risk of osteonecrosis remains even after people go off the drugs. The half-life of a drug describes how long it takes for half of it to be eliminated from the bloodstream.

The USC study is not the last word on the frequency of osteonecrosis of the jaw in people taking bisphosphonates. A much larger study is needed; ideally, one that takes place in many dental schools. Researchers at other institutions are trying to determine the prevalence of osteonecrosis of the jaw in cancer patients treated with bisphosphonates for cancer metastases. In the journal Bone, Dr. I.R. Reid, University of Auckland, estimated that it is 5% among people with myeloma, breast cancer or prostate cancer.

What to do

Thirteen years after Fosamax was launched, severe adverse effects have been showing up that may not be as rare as the public has been led to believe. Last year, the FDA reported that all bisphosphonates carry the risk of severe and sometimes incapacitating musculoskeletal pain. And case reports in several medical journals describe an unusual type of severe fracture of the femur associated with bisphosphonate use. In 2007 an increase in serious cases of atrial fibrillation was reported in people given the relatively new once-a-year bisphosphonate injection for fracture prevention (Zometa).

Osteonecrosis Treatments

As for osteoporosis of the jaw, more information is needed about how to prevent and treat it successfully—if that’s possible. Sedghizadeh and colleagues at USC Dental School did not have too much to offer on this topic. They advise unnamed alternate treatment options be considered for “nonnecessary extractions;” reducing the amount of the bacteria with a chlorhexidine rinse for those who must undergo a procedure; and daily antibiotics for those with denture trauma. For the exposed bone that fails to heal, the researchers name a procedure called “mucosal coverage.”

University of New Zealand’s Dr. Reid put it more succinctly “Management focuses on prevention, treatment of infection and cessation of bisphosphonate. The role of surgery is unclear.”

It can take years to learn the full range of serious adverse reactions to prescription drugs. That point was driven home last month when, in one issue of the journal Archives of Internal Medicine, several studies revealed new-found harms. The popular diabetes drugs, Actos and Avandia, increase the chance of having a fracture. Fosamax and other drugs in the class known as bisphosphonates, widely prescribed for osteoporosis since 1995 to prevent fractures, can cause an irregular heartbeat called atrial fibrillation. And postmenopausal hormone drugs, once aggressively urged for all women over 50 to prevent heart attacks and strokes actually cause strokes in some women, regardless of the type of hormone regimen or when it was started.

You get the picture: the drugs taken to prevent one major health problem can often cause another. The editorial that accompanied these new studies offered the excellent suggestion that doctors should quantify the benefits and risks so their patients can fully understand what they are getting into once they are told to go on long-term drug therapy. If, say, a bone drug helps only one in 100 women avoid a hip fracture and the same drug causes a potentially fatal atrial fibrillation in one in 100, then it’s a wash.

Jerry Avorn, MD, and William H. Shrank, MD, Harvard Medical School, offered a more immediate suggestion for avoiding drug-related injuries that targets people over the age of 65 years, the group with a high prevalence of adverse drug reactions. In a recent issue of the British Medical Journal, Avorn and Shrank wrote, “When an elderly person experiences an adverse drug reaction, it may be mistakenly attributed by the patient or doctor to a new disease or (even worse) the aging process itself. Examples include the parkinsonian side effects of many antipsychotic drugs and the fatigue, confusion, or depression-like symptoms that can result from excessive use of heavily marketed psychoactive drugs.”

Avorn and Shrank go on to describe what they called an opportunity for “total cure” by stopping the offending drug or lowering its dose. “In our own practices we have often seen patients on a seemingly inexorable trajectory towards institutional care whose functional capacity was restored by thoughtful reassessment of their drug regimens. This has led to the useful if overstated recommendation that any new symptoms in an older patient should be considered a possible drug side effect until proved otherwise.”